|Presenter:Dr Pilar BlancafortAssociate Professor
Cancer Epigenetics Group
School of Anatomy, Physiology and Human Biology
The University of Western Australia
Re-wiring the cancer genome: engineering of novel targeted therapies for breast and ovarian cancers
26 September 2013
|Abstract:Recently, the genomes of thousands of cancer patients have been resolved at single base pair resolution, which has delineated the aberrant landscape of mutations, deletions and copy number amplifications that characterize the intrinsic subtypes of cancers. By integrating this information with cancer transcriptomes and DNA methylomes, a discrete number of genomic loci involved in cancer initiation and metastatic progression have been identified. Major cancer drivers include molecules such as transcription factors (e.g MYC) and small GTPases (e.g KRAS) for which there is currently no small molecule specific inhibitors. In addition, the cancer genome project has identified other elusive targets not involved in proliferative capacity, but in residual disease, drug resistance and in tumor-stromal interactions.With this integrated knowledge of the cancer genome we have developed novel precision molecular medicine strategies to selectively revert or reprogram the aberrant gene expression and epigenetic state of prospective cancer drivers in breast and ovarian tumors. We deployed state of the art molecular biology and structural biology approaches to engineer a novel generation of sequence-specific DNA-binding molecules with the capacity to recognize the cancer genome with single locus selectivity. These engineered DNA-binding domains (DBDs, for example made of zinc fingers, transactivator-like effector TALEs and other backbones) are designed to bind promoters, enhancers and other regulatory regions controlling the expression of the targeted loci. These DBDs are linked to effector domains able to modify and edit chromatin, for example by inducing DNA methylation or by promoting irreversible DNA damage in specific oncogenic loci. The active proteins and small peptide variants are encapsulated using nanoparticles to target the delivery of our agents in breast and ovarian cancer models. The nanoparticles incorporate both targeted ligands for tumor targeting, imaging modalities, which allow the in vivo detection of the particles using MRI and other approaches. The outcomes of our research are the generation of novel state of the art nanoparticles for short-term clinical trials for the treatment of fatal diseases, such as metastatic ovarian cancer, and the discovery of novel therapeutic agents for these malignancies.
Professor Pilar Blancafort did her BsC at the University of Barcelona, and her PhD in the University of Montreal in the field of Biochemistry in 1999. She pursued her post-doc at the Scripps Research institute in the field of genome-engineering. In 2005 she started her own laboratory at the University of North Carolina at Chapel Hill, as Assistant professor and later as tenured Associate professor in 2011. In 2012, Professor Blancafort moved her laboratory at the University of Western Australia. Prof. Blancafort is a world specialist in genome engineering and gene targeting and her laboratory has pioneered the development of engineered DNA binding proteins to modulate the epigenetic state of cancer cells and delivery strategies for pre-clinical trials and tumor targeting. She has received several awards, including department of Defense breast cancer program, American Lung Association, several cancer nanotechnology, NCI/NIH awards and she is currently a Cancer Council of Western Australia Research Fellow.